Chemotherapeutic cure of metastatic breast cancer is prevented by the inablility to kill drug-resistant breast cancer cells because their apoptosis cell death pathway is usually blocked. Also, the severe reduction of ATP that causes necrosis cell death is not achieved since chemotherapy alone only modestly reduces ATP levels in drug-resistant cells. However, a new approach[unreadable]co-administration systematically of multiple ATP- depleting agents with chemotherapy q 2 weeks x 3[unreadable]further reduces the ATP to cancer cell-killing levels that produces drug-resistant partial tumor regressions with minimal toxicity in vivo. Concomitant blockade of multiple ATP-producing pathways is necessary to attain the very severe degree of ATP depletion necessary to kill cancer cells under in vivo conditions because ATP is generated by multiple metabolic pathways. Selectivity occurs because tumors are more sensitive to ATP depletion than normal tissues since tumors make more ATP and consume (deplete) more ATP. Aim 1 compares partial tumor regression (PR) rates treated by different non-toxic 5- and 6-member ATP-depleting combinations to determine the therapeutically "best" against drug-resistant breast cancer xenografts. Aim 2 evaluates nadir ATP levels in tumors treated in vivo by the "best" for correlation with PR rates as "proof-of-principle." Aim 3 evaluates the primary mode of treatment-induced cell death. Aim 4 evaluates the long-term therapeutic effects (cures?) of Aim 1's optimal cytocidal-inducing treatment over a one year period in drug-resistant xenografts as a guide to appropriate clinical trial. In the clinic, enhanced therapeutic efficacy should be obtained with markedly fewer toxic side- effects since the anticancer agents are employed at half the usual clinical dose. If validated clinically, the proposed therapy will open the way for cure of metastatic breast cancer, and the therapeutic strategy likely will apply to other drug-resistant types of cancer.